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Effects of targeting the VEGF and PDGF pathways in diffuse orthotopic glioma models
Anna C Navis1, Bob C Hamans, An Claes
1Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Abstract:
Currently available compounds that interfere with VEGF-A signalling effectively inhibit angiogenesis in gliomas, but influence diffuse infiltrative growth to a much lesser extent. Development of a functional tumour vascular bed not only involves VEGF-A but also requires platelet-derived growth factor receptor-β (PDGFRβ), which induces maturation of tumour blood vessels. Therefore, we tested whether combined inhibition of VEGFR and PDGFRβ increases therapeutic benefit in the orthotopic glioma xenograft models E98 and E473, both displaying the diffuse infiltrative growth that is characteristically observed in most human gliomas. We used bevacizumab and vandetanib as VEGF(R) inhibitors, and sunitinib to additionally target PDGFRβ. We show that combination therapy of sunitinib and vandetanib does not improve therapeutic efficacy compared to treatment with sunitinib, vandetanib or bevacizumab alone. Furthermore, all compounds induced reduction of vessel leakage in compact E98 tumour areas, resulting in decreased detectability of these mostly infiltrative xenografts in Gd-DTPA-enhanced MRI scans. These data show that inhibition of VEGF signalling cannot be optimized by additional PDGFR inhibition and support the concept that diffuse infiltrative areas in gliomas are resistant to anti-angiogenic therapy.
Insights
Combining anti-angiogenic therapies targeting VEGF and PDGFRβ does not improve glioma treatment efficacy. Diffuse infiltrative glioma growth remains resistant to anti-angiogenic strategies, highlighting limitations in current therapeutic approaches.
Area of Science:
- Oncology
- Cancer Biology
- Medical Research
Background:
- Vascular Endothelial Growth Factor A (VEGF-A) signaling is crucial for angiogenesis in gliomas.
- Platelet-Derived Growth Factor Receptor Beta (PDGFRβ) is involved in tumor blood vessel maturation.
- Current anti-angiogenic therapies targeting VEGF-A show limited efficacy against diffuse infiltrative glioma growth.
Purpose of the Study:
- To investigate if combined inhibition of VEGFR and PDGFRβ enhances therapeutic benefit in orthotopic glioma xenograft models.
- To evaluate the efficacy of targeting both angiogenesis and tumor vascular maturation in gliomas.
Main Methods:
- Utilized orthotopic glioma xenograft models (E98 and E473) exhibiting diffuse infiltrative growth.
- Administered VEGF(R) inhibitors (bevacizumab, vandetanib) and a dual VEGFR/PDGFRβ inhibitor (sunitinib).
- Assessed therapeutic efficacy and changes in tumor vascularization using Gd-DTPA-enhanced MRI.
Main Results:
- Combination therapy with sunitinib and vandetanib did not improve therapeutic efficacy compared to monotherapies.
- All tested compounds reduced vessel leakage in compact tumor areas.
- Gd-DTPA-enhanced MRI showed decreased detectability in infiltrative xenografts following treatment.
Conclusions:
- Combined inhibition of VEGFR and PDGFRβ does not offer additional therapeutic benefit over single-agent anti-VEGF therapy in these glioma models.
- Diffuse infiltrative glioma areas demonstrate resistance to anti-angiogenic therapy.
- Optimizing VEGF signaling inhibition cannot be achieved through additional PDGFR inhibition.
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